INDICATIONS

Travelers’ Diarrhea

AEMCOLO is indicated for the treatment of travelers’ diarrhea (TD) caused by non-invasive strains of
Escherichia coli in adults.

Limitations Of Use

AEMCOLO is not indicated in patients with diarrhea complicated by fever or bloody stool or due to
pathogens other than noninvasive strains of Escherichia coli [see WARNINGS AND PRECAUTIONS , Clinical Studies].

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AEMCOLO
and other antibacterial drugs, AEMCOLO should be used only to treat or prevent infections that are
proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility
information are available, they should be considered in selecting or modifying antibacterial therapy. In
the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric
selection of therapy.

Dosage

DOSAGE AND ADMINISTRATION

Basic Dosing Information

The recommended dose of AEMCOLO is 388 mg (two tablets) orally twice daily (in the morning and
evening) for three days. Take each dose with a glass of liquid (6-8 ounces). Do NOT take AEMCOLO
concomitantly with alcohol. AEMCOLO can be taken with or without food.

Important Administration Instructions

AEMCOLO must be taken orally. Swallow the tablets whole. Do NOT crush, break or chew the
delayed-release tablets.

HOW SUPPLIED

Dosage Forms And Strengths

AEMCOLO is a yellow-brown, ellipsoidal, film-coated, delayed-release tablet debossed on one side
with “SV2”. Each delayed-release tablet contains 194 mg of rifamycin.

Storage And Handling

AEMCOLO delayed-release tablets contain194 mg of rifamycin (equivalent to 200 mg of rifamycin
sodium), and are yellow brown, ellipsoidal and film coated. These are packaged in blister cards of 12
tablets contained in a cardboard carton. They are supplied as follows:

SIDE EFFECTS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.

The safety of oral AEMCOLO 388 mg twice daily was assessed in 619 adults with travelers’ diarrhea
in two controlled clinical trials (Trial 1 and Trial 2) with 96% of patients receiving three or four days of
treatment. These patients had a mean age of 36.2 years (range 18 to 87 years) with 7% ≥ 65 years
old; 49% were male, 84% were White, and 4% were Hispanic.

Discontinuation of AEMCOLO due to adverse reactions occurred in 1% of patients. The most frequent
adverse reactions leading to discontinuation of AEMCOLO were abdominal pain (0.5%) and pyrexia
(0.3%).

In Trial 1 (placebo-controlled), the adverse reaction that occurred in at least 2% of AEMCOLO-treated
patients (n = 199) and with an incidence higher than in the placebo group was constipation (3.5%
AEMCOLO, 1.5% placebo)

In Trial 2 (active comparator), the adverse reaction that occurred in at least 2% of AEMCOLO-treated
patients (n = 420) and with an incidence higher than in the ciprofloxacin group was headache (3.3%
AEMCOLO, 1.9% ciprofloxacin)

Adverse reactions reported in <2% of patients receiving AEMCOLO 388 mg twice daily with a higher
incidence than the comparator group was dyspepsia.

DRUG INTERACTIONS

No clinical Drug-Drug Interactions (DDIs) have been studied. Based on the minimal systemic
rifamycin concentrations observed after the recommended dose of AEMCOLO, clinically relevant
DDIs are not expected [see CLINICAL PHARMACOLOGY]

Warnings & Precautions

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Risk Of Persistent Or Worsening Of Diarrhea Complicated By Fever And/Or Bloody Stool

AEMCOLO was not shown to be effective in patients with diarrhea complicated by fever and/or
bloody stool. Patients with these conditions treated with AEMCOLO had prolonged time to last
unformed stool (TLUS). The effectiveness of AEMCOLO in travelers’ diarrhea caused by pathogens
other than E. coli has not been demonstrated. AEMCOLO is not recommended for use in patients
with diarrhea accompanied by fever or bloody stools or due to pathogens other than noninvasive
strains of E. coli [see INDICATIONS, Clinical Studies].

Clostridium Difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial
agents, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial
agents alters the normal flora of the colon which may lead to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing strains of C. difficile may cause increased morbidity and mortality, as these infections can
be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all
patients who present with diarrhea following antibacterial drug use. Careful medical history is
necessary since CDAD has been reported to occur over two months after the administration of
antibacterial agents.

If CDAD is suspected or confirmed, antibacterial drug use not directed against C. difficile may need to
be discontinued. Appropriate fluid and electrolyte management, protein supplementation, specific
antibiotic treatment of C. difficile, and/or surgical evaluation should be instituted as clinically indicated.

Development Of Drug-Resistant Bacteria

Prescribing AEMCOLO in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

No carcinogenicity studies have been conducted in animals with rifamycin.

Mutagenesis

Impairment Of Fertility

No fertility studies have been conducted in animals with rifamycin.

Use In Specific Populations

Pregnancy

Risk Summary

There are no available data on AEMCOLO use in pregnant women to inform any drug associated
risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Systemic absorption
of AEMCOLO in humans is negligible following oral administration of the recommended dose of
AEMCOLO [see CLINICAL PHARMACOLOGY]. Due to the negligible systemic exposure, it is not
expected that maternal use of AEMCOLO will result in fetal exposure to the drug.

In animal reproduction studies, no malformations were observed in pregnant rats or rabbits at
exposures 25,000 and 500 times (based on AUC), respectively, the human exposure achieved with
the recommended clinical dose of AEMCOLO. Treatment of pregnant rats with AEMCOLO at more
than 1,000 times the maximum plasma concentration (Cmax) and 25,000 times the systemic exposure
(based on AUC) during the period of organogenesis resulted in maternal toxicity, decreased fetal
weight, and variations in diaphragm formation. Similarly, treatment of pregnant rabbits with
AEMCOLO at more than 10 times the maximum human plasma concentration (Cmax), resulted in
maternal toxicity, decreased fetal weight, and slightly delayed fetal ossifications [See Data].

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S.
general population, the estimated risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2 to 4% and 15 to 20%, respectively. Advise pregnant women of the potential risk to a
fetus.

Animal Data

Embryofetal toxicity studies in rats and rabbits did not show malformations up to the maximum tested
doses of 855 and 85.5 mg/kg, (25,000 and 500 times greater plasma exposure based on AUC),
respectively, of rifamycin given orally during the period of organogenesis (gestational days 6-17/18).
In rats, the high dose of 855 mg/kg/day caused reduction in maternal food consumption, reduced fetal
weight and a higher number of fetuses with thin tendinous diaphragm. In rabbits, the high dose of
85.5 mg/kg/day caused a reduction in food consumption and bodyweight gain in pregnant dams, as
well as reduced fetal weights and slight delay in ossification, including slightly higher incidences of
fetuses with skull suture bone variations, enlarged skull fontanelle and incompletely ossified digit 5
medialphalanx of both forelimbs. No adverse fetal effects were observed in rats and rabbits
administered lower doses of oral rifamycin.

Lactation

Risk Summary

There is no information regarding the presence of AEMCOLO in human milk, the effects on the
breastfed infant, or the effects on milk production. Systemic absorption of AEMCOLO in humans is
negligible following oral administration of the recommended dose of AEMCOLO; therefore, exposure
to a breastfed infant through breastmilk is expected to be negligible [see CLINICAL PHARMACOLOGY]. There are no animal lactation data following oral rifamycin administration. Following single
intravenous injection of rifamycin to lactating ewes, rifamycin has been shown to pass into milk.1

The developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for AEMCOLO and any potential adverse effects on the breast-fed infant from
AEMCOLO or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of AEMCOLO has not been established in pediatric patients less than
18 years of age with travelers’ diarrhea.

Geriatric Use

Clinical studies with AEMCOLO for travelers’ diarrhea did not include sufficient numbers of patients
aged 65 and older to determine whether they respond differently than younger subjects. Other
reported clinical experience has not identified differences in responses between the elderly and
younger patients.

Renal Impairment

The pharmacokinetics of AEMCOLO in patients with impaired renal function has not been studied.
Given the minimal systemic exposure of rifamycin (taken as AEMCOLO) and minor role of renal
excretion in elimination of rifamycin, renal impairment is not expected to have a clinically meaningful
effect on rifamycin systemic exposure necessitating a dose adjustment.

Hepatic Impairment

The pharmacokinetics of AEMCOLO in patients with impaired hepatic function has not been studied.
Given the minimal systemic exposure of rifamycin (taken as AEMCOLO) hepatic impairment is not
expected to have a clinically meaningful effect on rifamycin systemic exposure necessitating a dose
adjustment.

OVERDOSE

No specific information is available on the treatment of overdose with AEMCOLO. In the case of
overdose, discontinue AEMCOLO, treat symptomatically, and institute supportive measures as
required.

CONTRAINDICATIONS

AEMCOLO is contraindicated in patients with a known hypersensitivity to rifamycin, any of the other
rifamycin class antimicrobial agents (e.g. rifaximin), or any of the components in AEMCOLO.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

Rifamycin is an antibacterial drug [see Microbiology].

Pharmacodynamics

AEMCOLO exposure-response relationships and time course of pharmacodynamic response are
unknown.

Pharmacokinetics

Plasma Concentrations

In healthy adults receiving the recommended dose of 388 mg rifamycin (taken as AEMCOLO) twice
daily for 3 days, the maximum observed rifamycin concentration in plasma was 8.72 ng/mL (6 hours
after the last dose). A majority (67%) of rifamycin concentrations in plasma were below the limit of
quantification (< 2 ng/mL) at this time point.

Absorption

Rifamycin (taken as AEMCOLO) has limited systemic exposure after oral administration of the
recommended dosage. Based on total urinary excretion data, bioavailability was < 0.1% under fasting
conditions.

Food Effect

A food-effect study involving administration of AEMCOLO to healthy volunteers under a fasted state
and with a meal (approximately 1,000 kcal including 500 kcal from fat) indicated that food decreased
systemic exposure of rifamycin. The decrease in systemic exposure of rifamycin is not expected to be
clinically relevant [see DOSAGE AND ADMINISTRATION].

Distribution

Plasma protein binding was approximately 80% in vitro. Binding was primarily to albumin and was
inversely proportional to concentration.

Elimination

The apparent half-life of orally administered rifamycin (taken as AEMCOLO) in plasma is unknown.

Metabolism

Cytochrome P450 (CYP) based metabolism of rifamycin was not observed in vitro.

Excretion

After a single oral dose of 400 mg AEMCOLO (388 mg rifamycin base) in fasting healthy adults, fecal
excretion of rifamycin was on average 86% of the nominal dose.

Specific Populations

The pharmacokinetics of rifamycin (taken as AEMCOLO) in patients with impaired renal or hepatic
function have not been studied.

Drug Interaction Studies

Clinical drug-drug interaction studies of rifamycin (taken as AEMCOLO) have not been conducted.

In Vitro Transporter Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

Rifamycin is a substrate of P-glycoprotein (P-gp) and anticipated to be an inhibitor of P-gp and breast
cancer resistant protein (BCRP) in the gut.

Rifamycin is an inhibitor of renal transporters organic anion transporter (OAT) 3, multidrug and toxin
extrusion (MATE) 1, and MATE2-K transporters in vitro, however, based on systemic concentrations
of rifamycin observed after administration of the recommended dose, clinically relevant inhibition of
these transporters in vivo is unlikely.

In Vitro Cytochrome P450 (CYP) Studies Where Drug Interaction Potential Was Not Further Evaluated
Clinically

Rifamycin is an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5 in vitro, however, based
on systemic concentrations of rifamycin observed after administration of the recommended dose
clinically relevant inhibition of these enzymes in vivo is unlikely.

Rifamycin is an inducer of CYP3A4 and CYP2B6 but not CYP1A2 in vitro, however, based on
systemic concentrations of rifamycin observed after administration of the recommended dose,
clinically relevant induction of these enzymes in vivo is unlikely.

Rifamycin is not a substrate of CYPs 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4/5.

Microbiology

Mechanism Of Action

Rifamycin belongs to the ansamycin class of antibacterial drugs and acts by inhibiting the betasubunit
of the bacterial DNA-dependent RNA polymerase, blocking one of the steps in DNA
transcription. This results in inhibition of bacterial synthesis and consequently growth of bacteria.

Resistance

Resistance to rifamycin is associated with mutations in the RNA polymerase beta subunit. Among E.
coli strains, the spontaneous mutation frequency rate of rifamycin ranged from 10-6to 10-10 at 4x –
16x MIC; the mutation frequency was independent of rifamycin concentration. Increases in the
minimum inhibitory concentrations were observed both in vitro and while on treatment following
exposure to rifamycin. Cross-resistance between rifamycin and other ansamycins have been
observed.

Antibacterial Activity

Rifamycin has been shown to be active against most isolates of the following pathogen both in vitro and in clinical studies of travelers’ diarrhea:

Escherichia coli (enterotoxigenic and enteroaggregative isolates)

Clinical Studies

Travelers’ Diarrhea

The efficacy of AEMCOLO given as 388 mg orally, taken two times a day, for 3 days was evaluated in
one multi-center, randomized, double-blind, placebo-controlled trial in adults with travelers’ diarrhea.

Trial 1 (NCT01142089) was conducted at clinical sites in Guatemala and Mexico, and provides the
primary evidence for the efficacy of AEMCOLO. A second active-controlled trial (Trial 2 –
NCT01208922) conducted in India, Guatemala and Ecuador, provided supportive evidence for the
efficacy of AEMCOLO. Although patients with fever and/or bloody stool at baseline were to be
excluded from both trials, 18 subjects treated with AEMCOLO had fever and bloody diarrhea at
enrollment in Trial 2. Stool specimens were collected before treatment and 1 to 2 days following the
end of treatment to identify enteric pathogens. The predominant pathogen in both trials was E. coli.

The clinical efficacy of AEMCOLO was assessed using an endpoint of time to last unformed (watery
or soft) stool (TLUS) before achieving clinical cure. The endpoint of clinical cure was defined as two
or fewer soft stools and minimal enteric symptoms at the beginning of a 24-hour period or no
unformed stools at the beginning of a 48-hour period. Kaplan-Meier estimates of TLUS for the intentto-
treat (ITT) Population, which includes all randomized subjects, in Trial 1 (Figure 1) show that
AEMCOLO significantly reduced the TLUS compared to placebo (p=0.0008).

Figure 1: Kaplan-Meier Estimates of Time to Last Unformed Stool (TLUS) in Trial 1
(ITT Population)

Table 1 displays the median TLUS and the number of patients who achieved clinical cure for the ITT
population in Trial 1. The median duration of diarrhea was significantly shorter in patients treated with
AEMCOLO than in the placebo group. More patients treated with AEMCOLO were classified as
clinical cures than were those in the placebo group.

Table 1: Clinical Response in Trial 1 (ITT Population)

AEMCOLO
(N=199)

Placebo
(N=65)

Difference

P value

Median TLUS (hrs)

46.0

68.0

-22.0

p = 0.0008a

Clinical cure, n (%)

162 (81.4%)

37 (56.9%)

24.5%

p =0.0001b

ITT = Intent-to-Treat; TLUS = time to last unformed stool (in hours)alog-rank test. A 95% confidence interval for the difference in medians cannot be computed due to the amount of
censored observations in the placebo group.bchi-square test, 95% confidence interval on the difference is (11.3, 37.7).

The results of Trial 2 supported the results presented for Trial 1. In addition, this trial provided
evidence that AEMCOLO-treated subjects with fever and/or bloody diarrhea at baseline had
prolonged TLUS. [see WARNINGS AND PRECAUTIONS]